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The interaction of the diltiazem with oral and intravenous cyclosporine in rats

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Summary

This study investigated the effect of diltiazem on the bioavailability of oral and intravenous cyclosporine (CsA) in rats. While control rats received normal saline, experimental groups received 60 or 90 mg/kg diltiazem orally for 3 days. Each group divided into 2 equal groups that received a single oral dose or i.v. injection of CsA. Pharmacokinetic parameters were analyzed by nonparametric analysis of variance. Pretreatment with 60 or 90mg/kg diltiazem decreased the area under the blood CsA concentration-time curve (AUC) of oral CsA compared to control group (54.5% and 65.5% for AUC0–24, 57.6% and 62.2% for AUC0–∞, respectively, p<0.05). Mean CsA maximum concentration (Cmax) decreased from 0.4 + 0.1 μg/ml to 0.1 ±0.0 μg/mL in rats pretreated with 90mg/kg diltiazem (p<0.05). The absolute bioavailability after oral administration (Fp.o) in the 60 or 90mg/kg diltiazem groups were lower than the control group (9.6% and 8.5% versus 22.6%). Pretreatment with 90mg/kg but not 60mg/kg of diltiazem increased the AUC0−8, elimination half-life (t1/2 ) of intravenous CsA (116.0 %, 219.2 %, respectively, p<0.05) and decreased the intravenous CsA clearence (CLi.v) (62.9 %, p<0.05). Diltiazem decreased the bioavailability of oral CsA, while it increased the bioavailability of intravenous CsA. One must consider this interaction when administering oral or intravenous CsA concomitantly with diltiazem.

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References

  1. Combalbert J., Fabre I., Fabre G., Dalet I., Derancourt J., Cano J.P., Maurel P. (1989): Metabolism of cyclosporin A; IV: purification and identification of the rifampicin-inducible human liver cytochrome P-450 (cyclosporin A oxidase) as a product of P450IIIA gene subfamily. Drug. Metab. Dispos., 17, 197–207.

    CAS  PubMed  Google Scholar 

  2. Kronbach T., Fischer V., Meyer U.A. (1988): Cyclosporine metabolism in human liver: identification of a cytochrome P-450III gene family as the major cyclosporine- metabolizing enzyme explains interactions of cyclosporine with other drugs. Clin. Pharmacol. Ther., 43, 630–635.

    CAS  PubMed  Google Scholar 

  3. Kolars J.C., Schmiedlin-Ren P., Schuetz J.D., Fang C., Watkins P.B. (1992): Identification of rifampin-inducible P450IIIA4(CYP3A4) in human small bowell enterocytes. J. Clin. Invest., 90, 1871–1878.

    Article  CAS  PubMed  Google Scholar 

  4. Kolars J.C., Awni W.M., Merion R.M., Watkins P.B. (1991): First-pass metabolism of cyclosporin by the gut. Lancet., 338, 1488–1490.

    Article  CAS  PubMed  Google Scholar 

  5. Wu C.Y., Benet L.Z., Hebert M.F., Gupta S.K., Rowland M., Gomez D.Y., Wacher V.J. (1995): Differentiation of absorption and first pass gut and hepatic metabolism in humans: Studies with cyclosporine. Clin. Pharmacol. Ther., 58, 492–497.

    Article  CAS  PubMed  Google Scholar 

  6. Quijano R.F., Ohnishi N., Umeda K., Komada F., Iwakawa S., Okumura K. (1993): Effect of atropine on gastrointestinal motility and the bioavailability of cyclosporine A in rats. Drug. Metab. Dispos., 21, 141–143.

    CAS  PubMed  Google Scholar 

  7. Hebert M.F., Roberts J.P., Prueksaritanont T., Benet L.Z. (1992): Bioavailability of cyclosporine with concomitant rifampin administration is markedly less than predicted by hepatic enzyme induction. Clin. Pharmacol. Ther., 52, 453–457.

    CAS  PubMed  Google Scholar 

  8. Wu C.Y., Hebert M.F., Benet L.Z. (1993): Use of iv and oral drug levels from cyclosporine (CsA) with concomitant rifampin to differentiate gut absorption and metabolism [Abstract], Pharm. Res., 10, S-345.

    Google Scholar 

  9. First M.R., Schroeder T.J., Alexander J.W., Stephens G.W., Weiskittel P., Myre S.A., Pesce A.J. (1991): Cyclopsporine dose reduction by ketoconazole administration in renal transplant recipients. Transplantation., 51(2), 365–370.

    Article  CAS  PubMed  Google Scholar 

  10. Keogh A., Spratt P., McCosker C., Macdonald P., Mundy J., Kaan A. (1995): Ketoconazole to reduce the need for cyclosporin after cardiac transplantation. N. Engl. J. Med., 333, 628–633.

    Article  CAS  PubMed  Google Scholar 

  11. Slaughter R.L., Edwards D.J. (1995): Recent advances: The cytochrome P450 enzymes. Ann. Pharmacother., 29, 619–624.

    CAS  PubMed  Google Scholar 

  12. Bagnis C., Deray G. (1998): Calcium inhibitors in the management of hypersentive patients on cyclosporine. Arch. Mal. Coeur. Vaiss., 91 (4), 411–414.

    CAS  PubMed  Google Scholar 

  13. Yee G.C., McGuire T.R. (1990): Pharmacokinetics drug interactions with cyclosporin (Part II). Clin. Pharmacokinet., 19(5), 400–415.

    Article  CAS  PubMed  Google Scholar 

  14. Maggio T.G., Bartels D.W. (1988): Increased cyclosporine blood concentrations due to verapamil administration. Drug. Intell. Clin. Pharm., 22(9), 705–707.

    CAS  PubMed  Google Scholar 

  15. Kessler M., Netter P., Renoult E., Jonon B., Mur J.M., Trechot P., Dousset B. (1989): Influence Of nicardipine on renal function and plasma cyclosporin in renal transplant patients. Eur. J. Clin. Pharmacol., 36, 637–638.

    Article  CAS  PubMed  Google Scholar 

  16. Spoendlin M., Peters J., Welker H., Bock A., Thiel G. (1998): Pharmacokinetics interaction between oral cyclosporin and mibefradil in stabilized post-renal-transplant patients. Nephrol. Dial. Transplant., 13(7), 1787–1791.

    Article  CAS  PubMed  Google Scholar 

  17. Yee G.C., McGuire T.R. (1990): Pharmacokinetics drug interactions with cyclosporin (Part I). Clin. Pharmacokinet., 19(4), 319–332.

    Article  CAS  PubMed  Google Scholar 

  18. Martinez F., Pirson Y., Wallemacq P., van Ypersele de Strihou C. (1991): No clinically significant interaction between Ciclosporin and isradipine. Nephron., 59(4), 658–659.

    Article  CAS  PubMed  Google Scholar 

  19. Jones T.E., Morris R.G., Mathew T.H. (1997): Diltiazem-cyclosporin pharmacokinetic interaction-dose-response relationship. Br. J. Clin. Pharmacol., 44, 499–504.

    Article  CAS  PubMed  Google Scholar 

  20. Smith C.L., Hampton E.M., Pederson J.A., Pennington L.R., Bourne D. W. (1994): Clinical and medicoeconomic impact of the cyclosporine-diltiazem interaction in renal transplant recipients. Pharmacotherapy., 14(4), 471–481.

    CAS  PubMed  Google Scholar 

  21. Jones T.E., Morris R.G. (1996): Diltiazem does not always increase blood cyclosporin concentration. Br. J. Clin. Pharmacol., 42, 642–644.

    CAS  PubMed  Google Scholar 

  22. Koleva M.R., Stoychev T.S. (1995): Effects of nifedipine, verapamil and diltiazem on the enzyme-inducing activity of phénobarbital and beta-naphthoflavone. Gen. Pharmacol., 26(1), 225–228.

    CAS  PubMed  Google Scholar 

  23. Hedayati S., Bernareggi A., Rowland M. (1991): Absorption kinetics of cyclosporin in rats. J. Pharm. Pharmacol., 43, 122–124.

    Google Scholar 

  24. Lindberg-Freijs A., Karlsson M.O. (1994): Dose dependent absorption and linear disposition of cyclosporin a in rat. Biopharm. Drug. Dispos., 15(1), 75–85.

    Article  CAS  PubMed  Google Scholar 

  25. Bernareggi A., Rowland M. (1991): Physiologic modeling of cyclosporin kinetics in rat and man. J. Pharmacokinet. Biopharm., 19(1), 21–50.

    Article  CAS  PubMed  Google Scholar 

  26. Ohba M., Ohnishi N., Komada F., Iwakawa S., Okumura K. (1996): Effects of Clarithromycin on the bioavailability of cyclosporin in rats. Biol. Pharm. Bull., 19(5), 733–737.

    CAS  PubMed  Google Scholar 

  27. Murray M., Butler A.M. (1996): Enhanced inhibiton of microsomal cytochrome P450 3A2 in rat liver during diltiazem biotransformation. J. Pharmacol. Exp. Ther., 279, 1447–1452.

    CAS  PubMed  Google Scholar 

  28. Sutton D., Butler A.M., Nadin L., Murray M. (1997): Role of CYP3A4 in human hepatic diltiazem N-demethylation:inhibiton of CYP3A4 activity by oxidized diltiazem metabolites. J. Pharmacol. Exp. Ther., 282(1), 294–300.

    CAS  PubMed  Google Scholar 

  29. Maenpaa J., Ruskoaho H., Pelkonen O. (1989): Inhibiton of hepatic microsomal drug metabolism in rats by five calcium antagonists. Pharmacol. Toxicol., 64(5), 446–50.

    Article  CAS  PubMed  Google Scholar 

  30. Brage R., Cortijo J., Esplugues J., Esplugues J.V., Marti-Bonmati E., Rodriguez C. (1986): Effects of calcium channel blockers on gastric emptying and acid secretion of the rat in vivo. Br. J. Pharmacol., 89, 627–633.

    CAS  PubMed  Google Scholar 

  31. Wadhwa N.K., Schroeder T.J., O’Flaherty E., Pesce A.J., Myre S.A., First M.R. (1987): The effect of oral metoclopramide on the absorption of cyclosporine. Transplantation., 43(2), 211–213.

    Article  CAS  PubMed  Google Scholar 

  32. Ueda C.T., Lemaire M., Gsell G., Misslin P., Nussbaumer K. (1984): Apparent dose-dependent oral absorption of cyclosporin a in rats. Biopharm. Drug. Dispos., 5, 141–151.

    Article  CAS  PubMed  Google Scholar 

  33. Wacher V.J., Wong S., Wong H.T. (2002): Peppermint oil enhances cyclosporine oral bioavailability in rats: Comparison with D-α-tocopheryl poly(ethylene glycol 1000) Succinate (TPGS) and ketoconazole. J. Pharm. Sci., 91(1), 77–90.

    Article  CAS  PubMed  Google Scholar 

  34. Whalen R.D., Tata P.N.V., Burckart G.J., Venkataramanan R. (1999): Species differences in the hepatic and intestinal metabolism of cyclosporine. Xenobiotica., 29, 3–9.

    Article  CAS  PubMed  Google Scholar 

  35. Ptachcinski R.J., Venkataramanan R., Burckart G.J. (1986): Clinical pharmacokinetics of cyclosporin. Clin. Pharmacokinet., 11(2), 107–132.

    Article  CAS  PubMed  Google Scholar 

  36. Wagner O., Schreier E., Heitz F., Maurer G. (1987): Tissue distribution, disposition, and metabolism of cyclosporine in rats. Drug. Metab. Dispos., 15(3), 377–383.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology, Dokuz Eylul University, School of Medicine, Balcova, 35340, Izmir, Turkey

    Sule Kalkan MD (Assistant Professor of Pharmacology), Mukaddes Gumustekin, Oguz Aygoren, Yesim Tuncok, Ayse Gelal & Hulya Guven

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  1. Sule Kalkan MD
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Kalkan, S., Gumustekin, M., Aygoren, O. et al. The interaction of the diltiazem with oral and intravenous cyclosporine in rats. European Journal of Drug Metabolism and Pharmacokinetics 29, 119–123 (2004). https://doi.org/10.1007/BF03190586

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  • DOI: https://doi.org/10.1007/BF03190586

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